University of Dundee
100 years of suramin Wiedemar, Natalie; Hauser, Dennis A.; Mäser, Pascal
Published in: Antimicrobial Agents and Chemotherapy
DOI: 10.1128/AAC.01168-19
Publication date: 2020
Document Version Peer reviewed version
Link to publication in Discovery Research Portal
Citation for published version (APA): Wiedemar, N., Hauser, D. A., & Mäser, P. (2020). 100 years of suramin. Antimicrobial Agents and Chemotherapy, 64(3), 1-14. [e01168]. https://doi.org/10.1128/AAC.01168-19
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1 One Hundred Years of Suramin http://aac.asm.org/ 2 3 4 Natalie Wiedemar1,2, Dennis A. Hauser1,2 and Pascal Mäser1,2 5 6 7 1 Swiss Tropical and Public Health Institute on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre 8 Dept. Medical Parasitology and Infection Biology 9 Socinstrasse 57 10 4051 Basel 11 Switzerland 12 13 2 University of Basel 14 Petersplatz 1 15 4001 Basel 16 Switzerland Downloaded from
17 Abstract http://aac.asm.org/ 18 Suramin is a hundred years old and still being used to treat the first stage of acute human sleeping
19 sickness, caused by Trypanosoma brucei rhodesiense. Suramin is a multifunctional molecule with a
20 wide array of potential applications, from parasitic and viral diseases to cancer, snakebite and
21 autism. Suramin is also an enigmatic molecule: What are its targets? And how does it get into cells
22 in the first place? Here we provide an overview on the many different candidate targets of suramin, on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
23 discuss modes of action, and routes of cellular uptake. We reason that once the polypharmacology
24 of suramin is understood at the molecular level, new, more specific, and less toxic molecules can be
25 identified for the numerous potential applications of suramin.
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26 Suramin, the fruit of early medicinal chemistry http://aac.asm.org/ 27 When suramin was introduced for the treatment of African sleeping sickness in 1922, it was one of
28 the first anti-infective agents that had been developed in a medicinal chemistry program. Starting
29 from the antitrypanosomal activity of the dye trypan blue, synthesized in 1904 by Paul Ehrlich,
30 Bayer made a series of colorless and more potent derivatives. Molecule 205 was suramin (Figure 1),
31 synthesized by Oskar Dressel, Richard Kothe and Bernhard Heymann in 1916. Sleeping sickness on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
32 (also known as human African trypanosomiasis, HAT) was at the forefront of research at that time,
33 not a neglected disease as it is today, and the development of suramin was a breakthrough for the
34 emerging field of chemotherapy. While the history of suramin has been reviewed elsewhere (1), we
35 focus here on the many potential applications of suramin and its enigmatic mode of action.
36
37 Suramin as an antiparasitic drug
38 Suramin is still being used for the treatment of Trypanosoma brucei rhodesiense infections (2).
39 However, it does not cross the blood-brain barrier and therefore is administered only for the first,
40 hemolymphatic stage of sleeping sickness, when the trypanosomes have not yet invaded the
41 patient's CNS. The standard treatment regimen for suramin is an initial test dose of 4-5 mg/kg
42 followed by five weekly doses of 20 mg/kg (but not more than 1 g) injected i.v. (3). Suramin is also
43 used for Surra (mal de caderas), caused by T. evansi, in particular for the treatment of camels (4).
44 The treatment regimen is a single injection i.v. of 10 mg/kg suramin, i.e. about 6-10 g (4). In vitro,
45 suramin also has some activity against T. cruzi (5). However, it is not used for Chagas' disease, and
46 studies in mice even suggested that suramin would exacerbate the disease (6). In vitro activity of
47 suramin against Leishmania major and L. donovani has recently been described (7). Furthermore,
48 suramin blocks host cell invasion by the malaria parasite Plasmodium falciparum. This was
49 observed for both the invasion of erythrocytes by P. falciparum merozoites (8) and the invasion of
50 HepG2 hepatoma cells by P. falciparum sporozoites (9).
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51 Suramin had been in use for river blindness, caused by the filarial parasite Onchocerca http://aac.asm.org/ 52 volvulus (10). It acts on both microfilariae and, to a larger extent, on adult worms (11, 12).
53 However, suramin was subsequently replaced by the less toxic, and orally bioavailable, ivermectin
54 (13, 14). The adverse effects of suramin are indeed manifold, including nephrotoxicity,
55 hypersensitivity reactions, dermatitis, anemia, peripheral neuropathy and bone marrow toxicity (3,
56 15). But despite its potential toxicity, the lack of bioavailability, and absence of lead-like properties on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
57 (Figure 1), suramin has found a surprising variety of repurposing applications. Table 1 provides an
58 overview on the biological activities of suramin and Table 2 lists clinical trials performed with
59 suramin.
60
61 Suramin as an antiviral agent
62 The antiviral and antibacteriophage activities of suramin are known since the mid-20th century (19,
63 20). Soon after the discovery of retroviruses, suramin was found to inhibit retroviral reverse
64 transcriptase (21), which served as a rationale to test suramin against human immunodeficiency
65 virus (HIV). Suramin protected T-cells from HIV infection in vitro (22), and in AIDS patients it
66 reduced the viral burden in some of the study subjects; however, no improvement of the
67 immunological features and clinical symptoms was achieved (17, 23, 24). Later-on suramin was
68 found to inhibit host cell attachment through binding to the HIV-1 envelope glycoprotein gp120,
69 indicating that the in vitro protection against HIV infection is mediated through inhibition of viral
70 entry (25).
71 Suramin also inhibits the binding of Dengue virus to host cells through a direct effect on the
72 viral envelope protein (26). Inhibition of host cell attachment was also found for Herpes
73 simplex (27) and Hepatitis C viruses (28), which explained the previously reported protective
74 effects of suramin against in vitro herpes simplex infections (29) and in vivo infections of ducks
75 with Duck Hepatitis B Virus (30). Similar to the experience with HIV, suramin had initially been
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76 tested against Hepatitis viruses due to its inhibitory effect on the viral DNA polymerase (31, 32). http://aac.asm.org/ 77 But in a small clinical trial suramin was found to be ineffective and toxic in chronic active Hepatitis
78 B patients (18). Suramin neutralized enterovirus 71 (EV71) in cell culture and in a mouse model by
79 binding to capsid proteins (33–35).
80 Suramin also bears potential against emerging viruses. It was shown to inhibit both RNA
81 synthesis and replication in Chikungunya virus (36). In vitro suramin conferred protection if present on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
82 at the time of infection, and this was attributed to a reduction of viral host cell binding and
83 uptake (37). In the murine model suramin led to a reduction of pathognomonic lesions if injected
84 prior to Chikungunya infection (38). Suramin also inhibited host cell invasion by Ebola virus (39)
85 and Zika virus, even when added after viral exposure of the cell cultures (40).
86
87 Suramin against cancer
88 The first studies on the effects of suramin on neoplasms in animals were carried out in the 1940's;
89 mice engrafted with lymphosarcoma developed significantly smaller tumors when simultaneously
90 treated with suramin (41). In the 1970's it was shown that suramin can enhance the action of
91 cyclophosphamide and adriamycin in mice engrafted with Ehrlich carcinoma (42). A first clinical
92 trial with suramin was carried out in the 1980's in advanced-stage adrenal and renal cancer
93 patients (16). Around half of the patients showed either partial or minimal responses, none showed
94 complete remission. Nevertheless, a number of subsequent clinical trials with suramin were carried
95 out (Table 2). In particular, suramin was tested against prostate cancer (43–51), non-small cell lung
96 cancer (52), breast cancer (52), bladder cancer (53, 54) and brain tumors (55, 56). Most of these
97 studies were based on the potential of suramin to act as an antagonist of growth factors (57–59),
98 which are often overexpressed by tumors. In addition, suramin directly exhibits cytostatic activity
99 on cultured tumor cells (60–62). However, the initial clinical tests did not warrant the further
100 development of suramin as an anticancer monotherapy.
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101 Subsequent tests focused on suramin as a chemosensitizer, based on the findings that at sub- http://aac.asm.org/ 102 cytotoxic levels (<50 µM), it enhanced the efficacy of anticancer drugs such as mitomycin C, taxol
103 or doxorubicin in ex vivo cultures and in animal models (63–65). Suramin combined with taxol
104 inhibited invasiveness and prevented metastasis in a xenograft mouse model (66). Different
105 explanations are conceivable for the chemosensitizing effects of suramin on tumor cells, including
106 inhibition of telomerase (67) or inhibition of fibroblast growth factors and angiogenesis (68). A on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
107 phase II clinical study was performed in patients with advanced, drug-resistant, non-small cell lung
108 cancer treated with taxol or carboplatin; supplementation with nontoxic doses of suramin did not
109 overcome drug resistance (69). Randomized controlled studies to validate the use of suramin as a
110 chemosensitizer in chemotherapy-naive lung cancer patients remain to be performed. A
111 combination of estramustine, docetaxel and suramin gave promising results in hormone-refractory
112 prostate cancer patients (51).
113
114 Suramin as an antidote
115 Three of the many biological activities of suramin support a potential use as a protective agent: the
116 inhibition of thrombin, the inhibition of phospholipase A2, and the inhibition of purinergic
117 signaling. Several vipers possess toxins that mimic thrombin (70), perfidiously triggering the
118 coagulation cascade in the mammalian blood. Suramin not only inhibits thrombin itself (71) but
119 also the thrombin-like proteases of snake venom (72), and was therefore proposed as an antidote for
120 snakebite. Other common constituents of metazoan venoms are phospholipases A2 that convert
121 phospholipids into lysophospholipids. Again, suramin inhibits mammalian phospholipase A2 (73)
122 as well as the orthologs from snake venom (74–76) and bee venom (77), suggesting that it can act
123 as an antidote. A certain degree of protection from venoms by suramin was confirmed in mouse
124 models (77–79). The potential use of suramin as an antidote is attractive given the high global
125 burden of snakebites (80) and the current shortage of antivenom (81).
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126 Suramin's ability to block P2 purinergic, G protein-coupled receptors (82) may counteract http://aac.asm.org/ 127 the action of neurotoxins that trigger arachidonic acid signaling, e.g. via phospholipase A2
128 activity (83). A possible explanation is that suramin prevents the activation of ATP receptors at the
129 motor nerve ending, which otherwise would depress Ca2+ currents and reduce acetylcholine release
130 at the presynaptic membrane (84). Suramin was also proposed to serve as a neuroprotective
131 agent (85, 86), as an antidote for kidney toxicity during cancer chemotherapy (87) and, based on its on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
132 antiapoptotic effect, to protect from liver failure (88). Suramin also inhibits connexin channels of
133 the tight junction, thereby suppressing ATP release and protecting cells from pore-forming bacterial
134 toxins such as hemolysin (89). The suramin analogs NF340 and NF546 were cardioprotective in a
135 mouse model for heart graft rejection, presumably via inhibition of the purinergic G protein-coupled
136 receptor P2Y11 (90).
137
138 Further potential uses of suramin
139 Suramin was found to have beneficial effects in a rat arthritis model (91) and to suppress fear
140 responses in the rat (92). It also promoted the expansion of T cells during immunization of mice and
141 was therefore considered as a small molecule adjuvant for vaccination (93). Based on the cell
142 danger hypothesis, suramin has recently been tested for the treatment of autism spectrum disorders
143 (ASD). The cell danger hypothesis suggests that a systemic stress response, which involves
144 mitochondria and purinergic signaling, contributes to the development of psychopathologies like
145 autism. Suramin had been shown to act as an inhibitor of purinergic signaling (94) and
146 mitochondrial function (95), and was therefore proposed as a potential therapy for ASD (96). First
147 tests in mouse models showed correction of symptoms in juveniles (96) as well as in adults (97). A
148 first small human trial was carried out and, even though difficult to quantify, showed improvement
149 of ASD symptoms (98).
150
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151 (Too) many targets http://aac.asm.org/ 152 Suramin is a large molecule that carries six negative charges at physiological pH (Figure 1). It is
153 likely to bind to, and thereby inhibit, various proteins (99). Thus the many and diverse potential
154 applications of suramin reflect the polypharmacology of suramin. Indeed, a large number of
155 enzymes have been shown to be inhibited by suramin (Table 3). Suramin inhibits many glycolytic
156 enzymes (100, 101), enzymes involved in galactose catabolism (PubChem BioAssay: 493189) and on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
157 enzymes of the Krebs cycle (102). Suramin further decreases the activity of a large number of
158 enzymes involved in DNA and RNA synthesis and modification: DNA polymerases (103, 104),
159 RNA polymerases (103, 105, 106), reverse transcriptase (21, 103), telomerase (67), and enzymes
160 involved in winding/unwinding of DNA (107, 108) are inhibited by suramin, as well as histone- and
161 chromatin modifying enzymes like chromobox proteins (109), methyltransferases (110) and sirtuin
162 histone deacetylases (111). Suramin is also an inhibitor of other sirtuins (112) and protein kinases
163 (113, 114), glutaminase (PubChem BioAssay: 624170), phospholipase A2 (115, 116), protein
164 tyrosine phosphatases (117), lysozyme (118) and different serine- and cysteine-proteases (119–
165 121). For caspases, cysteine proteases involved in apoptosis, suramin was described to act as either
166 inhibitor or activator (122, 123). Suramin further inhibits the Na+,K+-ATPase and other ATPases
167 (124–126), certain classes of GABA receptors (127, 128), and several G protein-coupled
168 receptors (129) including P2 purinoceptors and follicle-stimulating hormone receptor (130, 131).
169 Suramin also showed inhibitory effects against components of the coagulation cascade (71, 132)
170 and the complement system (133–135), and against deubiquitinating enzymes (PubChem BioAssay:
171 504865; 463106). It also interacts with prion protein, inhibiting the conversion into the pathogenic
172 form PrPSc (136). Beside the many inhibitory activities, suramin also activates certain nuclear
173 receptors that act as transcription factors (137), and intracellular calcium channels (138).
174
175
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176 Enigmatic mechanisms of action against African trypanosomes http://aac.asm.org/ 177 Somewhat ironically, much less appears to be known about the targets of suramin in African
178 trypanosomes, where it has been in use for a century, than in tumor cells or viruses. Suramin was
179 shown to inhibit glycolytic enzymes of T. brucei with selectivity over their mammalian orthologues,
180 in particular hexokinase, aldolase, phosphoglycerate kinase and glycerol-3-phosphate
181 dehydrogenase (100). Intriguingly, the trypanosomal enzymes have higher isoelectric points (>9), on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
182 which is due to extra arginines and lysines that are absent in the mammalian orthologues (165).
183 These residues form positively charged, surface exposed 'hot spots' that were proposed to be bound
184 by the negatively charged suramin (100). Inhibition of trypanosomal glycolysis by suramin is in
185 agreement with the dose-dependent inhibition of oxygen consumption and ATP production
186 observed in trypanosomes isolated from suramin-treated rats (166). However, the glycolytic
187 enzymes of T. brucei are localized inside glycosomes (167), and it is unclear how suramin could
188 penetrate the glycosomal membrane, or if suramin could bind to glycolytic enzymes in the cytosol,
189 before they are imported into the glycosomes (168). Alternative targets proposed for the
190 trypanocidal effect of suramin are glycerophosphate oxidase (139, 169), a serine oligopeptidase
191 termed OP-Tb (170), and REL1 (171), the RNA-editing ligase of the trypanosome's kinetoplast. It is
192 unclear how suramin would pass the inner mitochondrial membrane, but suramin inhibited
193 oxidative phosphorylation in mitochondrial preparations of the trypanosomatid Crithidia
194 fasciculate (172). Suramin also appeared to inhibit cytokinesis in T. brucei, as indicated by the
195 finding that suramin treatment resulted in an increased number of trypanosomes with two
196 nuclei (173).
197
198 Uptake routes of suramin into cells
199 The negative charges of suramin (Figure 1) not only promote binding to various proteins, they also
200 prevent diffusion across biological membranes. However, the majority of targets (Table 3) are
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201 intracellular, and radiolabeled suramin was shown to be taken up by human endothelial and http://aac.asm.org/ 202 carcinoma cells (174, 175) and by T. brucei bloodstream forms (166, 176). Suramin is not a
203 substrate of P-glycoprotein (177), nor of any other known transporter. Thus suramin must be
204 imported by endocytosis. Mammalian cells can take up suramin in complex with serum albumin by
205 receptor-mediated endocytosis (178). This had originally also been thought to happen in T.
206 brucei (166). However, the trypanosomes do not take up albumin by receptor-mediated on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
207 endocytosis (179), and LDL (low density lipoprotein) was proposed to act as the vehicle
208 instead (176). Suramin bound to LDL and inhibited the binding and uptake of LDL, while LDL
209 enhanced the uptake of suramin in bloodstream-form T. brucei (176). In contrast, overexpression in
210 procyclic T. b. brucei of Rab4, a small GTPase involved in the recycling of endosomes, decreased
211 suramin binding and uptake without affecting LDL binding or uptake (180). In the same study,
212 overexpression of a mutant Rab5, which was locked in the active, GTP-bound form, increased LDL
213 uptake without affecting suramin uptake (180). These findings indicated that, at least in the
214 procyclic trypanosomes of the tsetse fly midgut, LDL and suramin are imported independently of
215 each other.
216 The development of genome-wide RNAi screens in bloodstream-form T. brucei combined
217 with next-generation sequencing offered new opportunities to address the genetics of drug
218 resistance. This approach identified genes, silencing of which reduced the sensitivity to
219 suramin (181). These included a number of genes encoding for endosomal and lysosomal proteins,
220 in agreement with uptake of suramin through endocytosis. The invariant surface glycoprotein
221 ISG75 was identified as a likely receptor of suramin since knock-down of ISG75 in bloodstream-
222 form T. brucei decreased suramin binding and suramin susceptibility (181). ISG75 is a surface
223 protein of unknown function whose abundance is controlled by ubiquitination (182). Thus, there
224 appear to be (at least) two pathways for receptor-mediated endocytosis of suramin in T. brucei
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225 bloodstream forms: either directly with ISG75 as the receptor or, after binding of suramin to LDL, http://aac.asm.org/ 226 together with the LDL receptor.
227
228 Conclusion
229 Suramin remains controversial. Is its polypharmacology a liability or an asset? Is it toxic or
230 protective? Dated or timeless? Whatever the verdict on suramin, there is hardly a molecule with as on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
231 many biological activities. The list of potential targets is indeed impressive, and the publication
232 stream on suramin is not stagnating. The large majority of papers is not about trypanosomes or
233 trypanosomiasis (Figure 2). The list of potential targets has to be taken with a grain of salt, though,
234 since the negative charges of suramin, and its promiscuity in protein binding, can cause all kinds of
235 artefacts. Suramin can dissolve matrigel (183), resulting in a false positive signal in cell-based
236 screening campaigns that use matrigel for support, e.g. for inhibitors of angiogenesis (183). On the
237 other hand, suramin's high affinity to albumin (184) may give false negative results in cell-based
238 tests that contain mammalian serum. But in spite of the various confounders, a number of different
239 drug-target interactions for suramin have been experimentally validated, and are directly supported
240 by crystal structures (Table 4).
241 Several routes of investigation on the bioactivities of suramin have culminated in clinical
242 trials with healthy volunteers (i.e. phase I) or patients (i.e. phases II and III; Table 2). Yet, to our
243 knowledge, none of these trials was a striking success, and it is unclear whether suramin will ever
244 find medical applications outside the field of parasitology. However, molecules that act in a similar
245 way than suramin may be identified via target-based screening once the mode of action is
246 understood – new molecules that are more specific, less toxic, and possess better pharmacological
247 properties than suramin. Thus it will be important to dissect the polypharmacology of suramin at the
248 molecular level. We hope that the compiled list of targets (Table 3) will serve this purpose.
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249 Acknowledgments http://aac.asm.org/ 250 We are grateful to the Swiss National Science Foundation for financial support and to Prof. Alan
251 Fairlamb for sharing insights into the possible molecular interactions of suramin. on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
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660 cell surface and inhibit PrPSc replication. J Cell Sci 118:4959–4973.
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673 in mouse peritoneal cavity cells. Cell Biochem Funct 35:358–363.
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737 purinoceptor antagonists suramin and reactive blue 2 in mouse hippocampal
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740 malaria parasite diadenosine tetraphosphate hydrolase. Sci Rep 6:19981.
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750 McMahon-Pratt D, Schultz PG, Horwich AL, Chapman E, Johnson SM. 2016.
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755 inhibited by a variety of approved drugs, natural products, and known bioactive
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758 Gibson WC, Postma JP, Borst P, Opperdoes FR. 1987. Common elements on the
759 surface of glycolytic enzymes from Trypanosoma brucei may serve as topogenic
760 signals for import into glycosomes. EMBO J 6:215–221.
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769 169. Fairlamb A. 1975. A study of glycerophosphate oxidase in Trypanosoma brucei.
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771 170. Morty RE, Troeberg L, Pike RN, Jones R, Nickel P, Lonsdale-Eccles JD, Coetzer
772 TH. 1998. A trypanosome oligopeptidase as a target for the trypanocidal agents
773 pentamidine, diminazene and suramin. FEBS Lett 433:251–256.
774 171. Zimmermann S, Hall L, Riley S, Sørensen J, Amaro RE, Schnaufer A. 2016. A novel
775 high-throughput activity assay for the Trypanosoma brucei editosome enzyme REL1
776 and other RNA ligases. Nucleic Acids Res 44:e24.
777 172. Roveri OA, Franke de Cazzulo BM, Cazzulo JJ. 1982. Inhibition by suramin of
778 oxidative phosphorylation in Crithidia fasciculata. Comp Biochem Physiol B 71:611–
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782 based profiling. PLoS Negl Trop Dis 12:e0006980.
783 174. Gagliardi AR, Taylor MF, Collins DC. 1998. Uptake of suramin by human
784 microvascular endothelial cells. Cancer Lett 125:97–102. on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
785 175. Baghdiguian S, Boudier JL, Boudier JA, Fantini J. 1996. Intracellular localisation of
786 suramin, an anticancer drug, in human colon adenocarcinoma cells: a study by
787 quantitative autoradiography. Eur J Cancer Oxf Engl 1990 32A:525–532.
788 176. Vansterkenburg EL, Coppens I, Wilting J, Bos OJ, Fischer MJ, Janssen LH,
789 Opperdoes FR. 1993. The uptake of the trypanocidal drug suramin in combination
790 with low-density lipoproteins by Trypanosoma brucei and its possible mode of
791 action. Acta Trop 54:237–250.
792 177. Sanderson L, Khan A, Thomas S. 2007. Distribution of suramin, an
793 antitrypanosomal drug, across the blood-brain and blood-cerebrospinal fluid
794 interfaces in wild-type and P-glycoprotein transporter-deficient mice. Antimicrob
795 Agents Chemother 51:3136–3146.
796 178. Baghdiguian S, Boudier JL, Boudier JA, Fantini J. 1996. Intracellular localisation of
797 suramin, an anticancer drug, in human colon adenocarcinoma cells: a study by
798 quantitative autoradiography. Eur J Cancer Oxf Engl 1990 32A:525–532.
799 179. Coppens I, Opperdoes FR, Courtoy PJ, Baudhuin P. 1987. Receptor-mediated
800 endocytosis in the bloodstream form of Trypanosoma brucei. J Protozool 34:465–
801 473.
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802 180. Pal A, Hall BS, Field MC. 2002. Evidence for a non-LDL-mediated entry route for the http://aac.asm.org/ 803 trypanocidal drug suramin in Trypanosoma brucei. Mol Biochem Parasitol 122:217–
804 221.
805 181. Alsford S, Eckert S, Baker N, Glover L, Sanchez-Flores A, Leung KF, Turner DJ,
806 Field MC, Berriman M, Horn D. 2012. High-throughput decoding of antitrypanosomal on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre 807 drug efficacy and resistance. Nature 482:232–236.
808 182. Zoltner M, Leung KF, Alsford S, Horn D, Field MC. 2015. Modulation of the Surface
809 Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes. PLoS
810 Pathog 11:e1005236.
811 183. Prigozhina NL, Heisel AJ, Seldeen JR, Cosford NDP, Price JH. 2013. Amphiphilic
812 suramin dissolves Matrigel, causing an “inhibition” artefact within in vitro
813 angiogenesis assays. Int J Exp Pathol 94:412–417.
814 184. Vansterkenburg EL, Wilting J, Janssen LH. 1989. Influence of pH on the binding of
815 suramin to human serum albumin. Biochem Pharmacol 38:3029–3035.
816 185. Lozano RM, Jiménez M, Santoro J, Rico M, Giménez-Gallego G. 1998. Solution
817 structure of acidic fibroblast growth factor bound to 1,3, 6-naphthalenetrisulfonate: a
818 minimal model for the anti-tumoral action of suramins and suradistas. J Mol Biol
819 281:899–915.
820 186. Huang H-W, Mohan SK, Yu C. 2010. The NMR solution structure of human
821 epidermal growth factor (hEGF) at physiological pH and its interactions with
822 suramin. Biochem Biophys Res Commun 402:705–710.
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823 187. Lima LMTR, Becker CF, Giesel GM, Marques AF, Cargnelutti MT, de Oliveira Neto http://aac.asm.org/ 824 M, Monteiro RQ, Verli H, Polikarpov I. 2009. Structural and thermodynamic analysis
825 of thrombin:suramin interaction in solution and crystal phases. Biochim Biophys
826 Acta 1794:873–881.
827 188. Jiao L, Ouyang S, Liang M, Niu F, Shaw N, Wu W, Ding W, Jin C, Peng Y, Zhu Y, on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre 828 Zhang F, Wang T, Li C, Zuo X, Luan C-H, Li D, Liu Z-J. 2013. Structure of severe
829 fever with thrombocytopenia syndrome virus nucleocapsid protein in complex with
830 suramin reveals therapeutic potential. J Virol 87:6829–6839.
831
832
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833 TABLES http://aac.asm.org/ 834
835 Table 1. Diseases and pathogens susceptible to suramin.
836
Activity in Activity in Activity in Disease, pathogen cell culture animal model patient on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
Parasitic infections T. b. rhodesiense HAT x x x T. b. gambiense HAT x x x Surra, T. evansi x x n.a. River blindness, O. volvulus x x x Trypanosoma cruzi x Leishmania spp. x Plasmodium falciparum x Viral infections Hepatitis x x x AIDS, HIV x x Herpes simplex x x Chikungunya x x Enterovirus 71 x x Dengue x Zika x Ebola x Neoplastic diseases Non-small cell lung cancer x x Breast cancer x x Bladder cancer x x Brain tumors x x Prostate cancer x x x Other uses Snake bite x x Arthritis x x Autism n.a. x x 837
838
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839 Table 2. Clinical trials with suramin. Trials with a registered NCT number are from http://aac.asm.org/ 840 ClinicalTrials.gov; others are from the literature.
841
Registry ID Disease Phase Year
NCT02508259 Autism spectrum disorders I, II 2015
NCT01671332 Non-small cell lung cancer II 2012 on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre NCT01038752 Non-small cell lung cancer II 2010 NCT00083109 Recurrent renal cell carcinoma I, II 2004 NCT00066768 Recurrent non-small cell lung cancer I 2003 NCT00054028 Recurrent breast cancer I, II 2002 NCT00006929 Recurrent non-small cell lung cancer II 2000 NCT00006476 Bladder cancer I 2000 NCT00004073 Brain and central nervous system tumors II 1999 NCT00002921 Adrenocortical carcinoma II 1997 NCT00003038 Advanced solid tumors I 1997 NCT00002723 Prostate cancer III 1996 NCT00002881 Prostate cancer III 1996 NCT00002652 Multiple myeloma and plasma cell neoplasm II 1995 NCT00002639 Brain and central nervous system tumors II 1995 NCT00001381 Bladder neoplasms, transitional cell carcinoma I 1994 NCT00001266 Prostatic neoplasm II 1990 NCT00001230 Filariasis observ. 1988 (16) Solid tumors observ. 1987 (17) AIDS observ. 1987 (18) Hepatitis B observ. 1987 842
843
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844 Table 3. Putative target proteins of suramin, biological processes and mechanisms. Suramin acts as http://aac.asm.org/ 845 an inhibitor or antagonist in all cases except for the pregnane X receptor and the ryanodine receptor.
846 The mode of action against caspase is controversial.
847
Putative target Reference
on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre Metabolism 6-Phosphofructokinase (100) Fructose-l,6-bisphosphate aldolase (100) Glucose-6-phosphate isomerase (100) Glyceraldehyde-3-phosphate dehydrogenase (100) Glycerol-3-phosphate dehydrogenase (100, 139) Glycerol kinase (100) Hexokinase (100) Phosphoglycerate kinase (100) Pyruvate kinase (101) Triose-phosphate isomerase (100) Succinic dehydrogenase (102) Galactokinase 493189* Glutaminase 624170* Glycerophosphate oxidase (139) Nucleoside triphosphate diphosphohydrolase 1 & 2 (125, 126, 140–143) Nucleotide pyrophosphatase/phosphodiesterase 1 & 3 (144)
Nucleic acids DNA polymerase alpha (103, 104) DNA polymerase beta (103, 104) DNA polymerase gamma (103) DNA polymerase delta (104) DNA polymerase I (103, 104) Terminal deoxynucleotidyltransferase (103) DNA primase (103) DNA dependent RNA polymerase (103, 106) RNA dependent RNA polymerase (105) Reverse transcriptase (21, 103) Telomerase (67) RNAse H (145) Flavivirus RNA helicase (40, 107, 146) DNA Topoisomerase II (108) Tyrosyl-DNA phosphodiesterase 1 (147) Human antigen R (148) DNA-binding protein MCM10 (149)
Epigenetics Chromobox protein homologue 1 beta 488953* Chromobox protein homologue 7 (109) Histone methyltransferases (110, 150) Precorrin-4 C(11)-methyltransferase (151) Sirtuin 1, 2, 5 (111, 112, 152)
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Protease http://aac.asm.org/ Kallikrein (121) Alpha Thrombin (71) Human neutrohphil cathepsing G (120) Human neutrophil elastase (120) Human neutrophil proteinase 3 (120) Rhodesain (119) Caspases 1, 2, 8, 9, 10 (122, 123, 153, 154) Falcipain-2 (155)
Extracellular matrix
Hyaluronidase (156, 157) on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre Iduronate sulfatase (157) -glucuronidase (157)
Membrane channels and signaling Non-junctional connexin 43 hemichannels (89) Na+,K+-ATPase (124) Cystic fibrosis transmembrane regulator (158) Ryanodine receptor 1 (138) GABAA receptors (127, 128) P2X Purinergic receptors (94) P2Y Purinergic receptors (94) N-methyl-D-aspartate receptor (159) DNA-dependent protein kinase (113) Protein kinase C (114) Protein tyrosine phosphatases (117) VIP receptor (129) Follicle-stimulating hormone receptor (131) Pregnane X receptor (137) Diadenosine tetraphosphate hydrolase (160)
Other Prion (PrpC) (136) Complement factors (121, 133–135)
Phospholipase A2 (116, 161) Lysozyme (118) Antimicrobial Peptide CM15 (162) Ubiquitin carboxyl-terminal hydrolases 1 & 2 504865; 463106* HSP 60 chaperonin system (163, 164) GroEL chaperonin system (163, 164) 848 *PubChem BioAssay, last retrieved 29.04.2019
849
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850 Table 4. Solved structures of suramin complexed to target proteins. http://aac.asm.org/ 851
PDB id Protein Reference
6CE2 Myotoxin I from Bothrops moojeni (75) 4YV5 Myotoxin II from Bothrops moojeni (74) 1Y4L Myotoxin II from Bothrops asper (116) on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre 3BJW Ecarpholin S from Echis carinatus (76) 1RML Acid fibroblast growth factor (185) n.a. Human epidermal growth factor (hEGF) (186) 4X3U CBX7 chromodomain (109) 3BF6, 2H9T Human thrombin (187) 2NYR Human sirtuin homolog 5 (112) 3PP7 Leishmania mexicana pyruvate kinase (101) 3GAN Arabidopsis thaliana At3g22680 n.a. 3UR0 Murine norovirus RNA-dependent RNA polymerase (105) 4J4V Pentameric bunyavirus nucleocapsid protein (188) 4J4R Hexameric bunyavirus nucleocapsid protein (188) 852
853
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854 FIGURE LEGENDS http://aac.asm.org/ 855
856 Figure 1. Suramin structure and medicinal chemistry parameters. Except for its good solubility in
857 water, suramin lacks lead-like properties as defined e.g. by Lipinsky's rule of 5.
858
859 Figure 2. Publications on suramin in PubMed. Cumulative numbers are shown for papers on on March 20, 2020 at Brought to you by the University of Dundee Library & Learning Centre
860 suramin and trypanosomes or trypanosomiasis (black, search term "trypanosom*"), cancer (red,
861 "cancer OR tumor"), viruses (yellow, "virus OR viral OR hiv OR aids"), and toxins (green, "toxin
862 OR venom"). Other papers on suramin are shown in beige. There is no saturation yet. And it is
863 surprising that only a minority of the publications on suramin actually deal with trypanosomes.
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